Since early in the twentieth century it has been recognized that the ionizing properties of x-rays allow them to be used for therapeutic and diagnostic purposes. However, treatment of tumors with x-rays is difficult because about the same x-ray dose is required to kill the cancerous cells as kills healthy cells. Therefore, techniques for concentrating the x-ray dose in the target area, with minimum dose to surrounding healthy tissue, are of basic importance in radiotherapy and radiosurgery.
An example of radiotherapy is illustrated in FIG. 1. Radiotherapy consists of bathing large volumes of the body 10 in direct radiation 20 generated from a conventional therapy x-ray source 30. Usually performed at 1 MeV or more, the goal is to damage both healthy and diseased cells. The healthy cells are better able to repair the damage and remain viable while the diseased cells die.
In recent years, photons with energy in excess of 1 MeV have been preferred for therapeutic purposes over the more traditional medical x-rays in the 50 to 100 keV band. This is because of several factors. First, the beam intensity drops less quickly as it passes through the body, yielding a more uniform dose at the target site. Second, the primary photoelectrons (which cause tissue damage) are created by Compton scattering of the high-energy photons and penetrate inward from the site of the interaction. This leads to low dose deposition at the skin, and a buildup effect inward. Third, because the beam absorption is dependent only on the density of the tissue, and not upon the composition, there is little interaction with bones.
In the last fifteen years, as computed tomography (CT) and magnetic resonance imaging (MRI) have improved imaging of the body, a new technique, known as radiosurgery, has been developed. Radiosurgery is illustrated in FIG. 2. Radiosurgery targets a specific part of the body, such as the head 12. By moving the x-ray source 30 through an arc as shown by the arrows 40, with the isocenter at the hub of the arc 40, the diseased tissue is given a higher dose than the healthy tissue. To achieve a lethal x-ray dose deep inside the body, the x-ray beam is brought to bear on the target tumor from a variety of directions, spreading the beam across as much healthy tissue as possible, but always remaining aimed at the target. This is done by creating dozens of narrow beams from radioactive decay (as in the case of the gamma knife) or by scanning an x-ray source across a series of arcs in the case of a linear accelerator (LINAC). Both techniques are effective and in general practice. However, even with these radiosurgical techniques, collateral damage to nearby tissue remains a major problem because the x-ray beams spread to the side and overshoot the target.
Contrast agents are currently used to enhance the x-ray visibility of soft tissue structures. The higher cross section that the heavy elements present to the x-rays used in medical applications allows this technique to be successful. This x-ray dose enhancement caused by the contrast agents has been viewed as a detrimental side effect of diagnostic imaging in the past because it causes cellular, particularly DNA, damage. Such concerns are discussed in the literature, mostly relating to angiography or excretory urography, two procedures that deliver exceptionally high diagnostic doses to the patient, as discussed by Callisen et al., Cochran et al., and Weber et al.
From concerns related to cell damage caused by the use of high doses of contrast agents came the idea that the damaging effects on cells could be used to improve radiotherapy. Several papers have discussed the use of contrast agents to enhance the effect of x-rays for tumor treatment and have demonstrated that enhancement works in several model systems. Hadnagy et al. showed that contrast agent alone or contrast agent combined with x-rays increased radiation-induced chromosomal aberrations in blood cells. The amount of aberration was dependent on iodine concentration. Fairchild et al. relates to theoretical considerations of the use of iodinated deoxyuridine as an enhancing agent for treating tumors. Santos Mello et al. refers to considerations and results relating to the therapeutic advantages of loading tumors in mice, particularly brain tumors, with iodine and treating them with low-energy photons. They achieved a dose enhancement of up to 3 in lymphocytes. Iwamoto et al. relates to use of low-energy x-rays and iodine to treat brain tumors in rabbits. They found a dose enhancement of about 30% by using the combination. Dawson et al. relates to treating cells in vitro with various concentrations of iodine. They found radiation enhancement of cell damage with an iodine concentration of 50 mg/ml. Cochran and Norman relates to findings of chromosome damage in patients subjected to nonionic contrast media. Iwamoto et al. (see also U.S. Pat. No. 5,008,907) discusses the use of a CT scanner and collimator, together with contrast agent, to treat brain tumors. In this report, the dose enhancement was determined to be about 50%. Cohen et al. relates to use of Gd-DTPA contrast agent to detect changes in microvascular characteristics in rats implanted with a tumor. Norman et al. relates to use of iodinated contrast agent together with x-rays for treating brain tumors. They also suggest using gadolinium as a contrast agent.
None of these references proposes a device specifically designed to make maximum use of the contrast agent to enhance x-ray therapy or x-ray surgery or specific methods therefor.
None of these references discusses methods to precisely calibrate the amount of contrast agent desired in a tumor nor methods to accurately deliver the amount of contrast agent necessary to produce a radiation dose enhancement of greater than 2:1 in the tumor over the normal tissues. None of these references discusses methods of treating only the surface of the tumor to destroy the tumor vasculature and also maintain a safe dose of radiation to the normal tissues.